Project summary Late-life depression (LLD) is a common mental disorder in the elderly, with high prevalence rates ranging from 1 to 5% (Byers et al., 2010). Recent evidence suggest that LLD is linked to age-related negative health outcomes, such as cerebrovascular disease, increased risk of Alzheimer?s disease, vascular dementia, and mortality. The mechanisms of LLD are complex and involve the dysregulation of different biological pathways. Based on past research conducted in our group, we identified dysregulation of proteostasis control as a potential pathophysiologic mechanism of LLD. Loss of proteostasis control can play a significant role in neuronal and axonal dysfunction, revealed by diffusion-tensor imaging, in LLD. Based on preliminary data and the current literature, this study proposes to evaluate the association between a newly developed proteostasis control (PC) index, clinical phenotypes (severity of depressive symptoms and cognitive impairment), and microstructural white matter abnormalities in older adults with depression. Our hypotheses are that LLD individuals will show a significantly higher PC index (i.e. indicating a greater proteostasis dysregulation) compared to age- and gender-matched never-depressed control subjects. Also, PC dysregulation will be associated with greater cognitive impairment, and decreased fractional anisotropy and increased radial diffusivity in LLD. To our knowledge, this will be the first study to examine the association between circulating proteostasis markers, microstructural changes and clinical characteristics in LLD. By gaining a better understanding of the molecular basis of structural changes in LLD, we can identify novel therapeutic targets and critical periods for intervention to treat depression in older adults.